Evaluation of changes in exhausted T lymphocytes and miRNAs expression in the different trimesters of pregnancy in pregnant women.

BACKGROUND: Throughout the three trimesters of a typical pregnancy, we looked at changes in the expression of miRNAs and exhausted T lymphocytes for this study. METHODS AND RESULTS: Fifty healthy subjects were included in this study. The frequency of exhausted T lymphocytes was measured in isolated PBMCs using flow cytometry. PD-1, TIM-3, and related miRNAs gene expression were assessed using qRT-PCR. The analyses revealed a significant decline in PD-1 and Tim-3 expression in PBMCs from RPL women (p = 0.0003 and p = 0.001, respectively). In addition, PD-1 and TIM-3 expression increased significantly in the 2nd trimester compared with the 1st trimester of healthy pregnant women (p < 0.0001 and p = 0.0002, respectively). PD-1 and TIM-3 expression was down-regulated in the 3rd trimester compared with the 1st and 2nd trimesters. In the present study, we demonstrated that TIM-3+/CD4+, TIM-3+/CD8+, PD-1+/CD4+, and PD-1+/CD8 + exhausted T lymphocytes increased in the circulation of women in the 2nd trimester compared to the 1st and 3rd trimester. In the 3rd trimester, the expression of miR-16-5p increased significantly (p < 0.0001). miR-125a-3p expression was down and upregulated in 2nd (p < 0.0001) and 3rd (p = 0.0007) trimesters compared to 1st trimester, respectively. This study showed a significant elevation of miR-15a-5p in 3rd trimester compared to 1st trimester of pregnant women (p = 0.0002). CONCLUSIONS: Expression pattern of PD-1 and TIM3 in exhausted T lymphocytes is different not only between normal pregnant and RPL women but also in different trimesters of pregnancy. So, our results showed the role of these markers in the modulation lymphocytes activity in different stages of pregnancy.

Docosahexaenoic acid (DHA) impairs hypoxia-induced cellular and exosomal overexpression of immune-checkpoints and immunomodulatory molecules in different subtypes of breast cancer cells.

BACKGROUND: Tumor cells express immune-checkpoint molecules to suppress anti-tumor immune responses. In part, immune evasion takes place by secreting exosomes bearing immune-checkpoint and immunomodulatory molecules and their inducing and/or regulating agents e.g., microRNAs (miRs). This study aimed to evaluate the effects of omega-3 fatty acid, docosahexaenoic acid (DHA), on the expression of some selected immune-checkpoint and immunomodulatory molecules and their regulating miRs under both normoxic and hypoxic conditions in triple negative (TNBC) invasive and triple positive non-invasive breast cancer cell lines. METHODS: MDA-MB-231 and BT-474 cells were treated with 100 µM DHA under hypoxic and normoxic conditions for 24 h. Exosomes were isolated by ultracentrifuge and confirmed by electron microscope and anti-CD9, -CD63, -CD81 immunoblotting. Total RNA from cells and exosomes were extracted and expression of CD39, CD73, CD47, CD80, PD-L1, B7-H3, B7-H4 genes and their related miRs were evaluated by quantitative Real-time PCR. RESULTS: This study showed significant over-expression of immune-checkpoint and immunomodulatory molecules under hypoxic condition. Treatment with DHA resulted in a significant decrease in immune-checkpoint and immunomodulatory molecule expression as well as an upregulation of their regulatory miRNA expression. CONCLUSION: DHA supplementation may be utilized in breast cancer therapy for down-regulation of cellular and exosomal immune escape-related molecules.

SIGNIFICANCE OF THE STUDY: This study showed anti-immunosuppressive effect of DHA on BC cell lines in normoxic and hypoxic conditions.

The evaluation of PD-1 and Tim-3 expression besides their related miRNAs in PBMCs of women with recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is a multifactorial disorder, associated with immunologic abnormalities. During pregnancy, the maternal immune system uses different tolerance mechanisms to deal with a semi-allogenic fetus. The expression of immune checkpoints and their related miRNAs in immune cells can ensure pregnancy at the feto-maternal interface by modulating immune responses. This study aims to evaluate the expression of the immune checkpoint molecules PD-1 and Tim-3 on circulating T cells by flow cytometry, that of mir-138 and mir-155 in PBMCs by Real-time PCR, and the concentrations of TGF-ß and IP-10 in the sera of women suffering from RPL as well as of gestational age-matched healthy pregnant women by ELISA. The percentage of PD-1 or Tim-3 expressing CD8+ T cells was significantly lower in RPL patients compared to the controls, while there was no significant difference in Tim-3 expression of CD4+ T cells between the two groups. The mRNA of both the PD-1 and Tim-3 genes were downregulated in PBMCs of RPL patients compared to controls, however, the difference was not statistically significant for Tim-3. The concentration of TGF-ß was significantly lower and that of IP-10 was significantly higher in the sera of RPL patients than in those of the controls. The relative expression of mir-138 and miR-155 were significantly lower, in PBMCs of RPL patients than in those of healthy pregnant women. These data confirm that by affecting cytokine production, immune checkpoints, and microRNAs play a role in establishing the appropriate local immune environment for successful pregnancy. The wider analysis of immune checkpoints may also yield new biomarkers for the diagnosis and prevention of RPL.

T Lymphocyte Characteristic Changes Under Serum Cytokine Deviations and Prognostic Factors of COVID-19 in Pregnant Women.

Physiological changes during pregnancy make the individuals more susceptible to severe respiratory diseases. Hence, pregnant women with coronavirus disease 2019 (COVID-19) are likely at a higher risk. We investigated the effects of COVID-19 on T cell response and serum cytokine profile in pregnant patients. Peripheral blood mononuclear cells (PBMCs) of women with COVID-19 were collected during the first trimester of pregnancy, and the percentage of total lymphocytes, as well as CD4 + and CD8 + T cells, was assessed using flow cytometry. The expression of the programmed death-1 (PD-1) marker for exhausted T cells was evaluated. Additionally, the serum samples were provided to evaluate the levels of antiviral and proinflammatory cytokines, as well as laboratory serological tests. Pregnant women with COVID-19 presented lymphopenia with diminished CD4 + and CD8 + T cells. Besides, high expression levels of the PD-1 gene and protein were observed on PBMCs and T cells, respectively, when compared with normal pregnant individuals. Moreover, serum levels of TNF-α, IL-6, IL-1ß, and IL-2 receptor were notably enhanced, while IFN-I α/ß values were significantly decreased in the patients when compared with controls. Furthermore, hyperlipidemia, hyperglycemia, and hypertension were directly correlated with the disease although serum albumin and vitamin D3 levels adversely affected the viral infection. Our study showed extreme lymphopenia and poor T cell response while elevated values of serum inflammatory cytokines in infected pregnant women. Moreover, a hypertension background or metabolic changes, including hyperlipidemia, hyperglycemia, and vitamin D3 or albumin deficiency, might be promising prognostic factors in pregnant women with COVID-19.

The association of Treg and Th17 cells development factors and anti-TPO autoantibodies in patients with recurrent pregnancy loss.

OBJECTIVES: Thyroid autoimmunity is considered as the most prevalent autoimmune condition in women in fertility age. There are different clinical evidences indicating the association between thyroid autoimmunity and increased risk of RPL. This study aimed to analyze the association of Tregs and Th17 cells development factors and anti-thyroid peroxidase (anti-TPO) antibodies in RPL patients. Healthy controls (n = 36), TPO + controls (n = 25) and TPO + RPL (n = 32) participated in this study. After blood sampling, the frequency of Th17 and Tregs was evaluated using flow cytometry. Real-time PCR and ELISA was used to assess the status of Tregs and Th17 related transcription factors and cytokines in mRNA and protein level, respectively. RESULTS: TPO + RPL group showed a higher Th17 frequency compared to healthy controls and TPO + controls groups (p = 0.0002 and p = 0.04, respectively). Additionally, mRNA expression levels of RORγT and IL-17 were significantly higher in TPO + RPL compared to healthy controls and TPO + controls groups. In contrast, Foxp3 and TGFß expression was lower in TPO + RPL. ELISA findings also indicated a significantly higher IL-17 and lower TGFß secretion in TPO + RPL compared to healthy controls and TPO + controls. Thyroid autoimmunity should intensely be controlled specially in patients with RPL history.

ctDNA as a novel and promising approach for cancer diagnosis: a focus on hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent forms of cancer worldwide. Therefore, it is essential to diagnose and treat HCC patients promptly. As a novel discovery, circulating tumor DNA (ctDNA) can be used to analyze the tumor type and the cancer location. Additionally, ctDNA assists the cancer stage determination, which enables medical professionals to provide patients with the most appropriate treatment. This review will discuss the HCC-related mutated genes diagnosed by ctDNA. In addition, we will introduce the different and the most appropriate ctDNA diagnosis approaches based on the facilities.

The effect of lymphocyte immunotherapy (LIT) in modulating immune responses in patients with recurrent pregnancy loss (RPL).

In order to prevent miscarriage in RPL patients, the goal of this study was to determine how well lymphocyte immunotherapy (LIT) works in modifying immunological responses produced by cells, cytokines, transcription factors, and microRNAs. 200 RPL patients and 200 healthy controls were included in the study. Using flow cytometry, it was possible to compare the frequency of cells before and after lymphocyte treatment. Real-time PCR was used to assess the gene expression levels of transcription factors, cytokines, and microRNAs. ELISA method was used to evaluate the level of secretion of cytokines in the serum. Primary evaluation of the immune profile between healthy controls and RPL cases showed a higher frequency of Th17, NK, B cells and a lower frequency of Treg cells in RPL cases. Also, pro-inflammatory cytokines showed increased expression at mRNA and protein levels in the RPL group in comparison with the control group. Whereas, anti-inflammatory cytokines showed decreased expression in RPL patients. Decreased and increased frequency of Th17 and Treg lymphocytes observed in RPL cases following LIT, respectively. The same results obtained for RORγt and FoxP3 mRNA expression as transcription factor of Th17 and Treg cells, respectively. NK cell cytotoxicity decreased after LIT in RPL patients. miR-326a and miR-155 expression after LIT reduced, but miR-146a and miR-10a expression increased in RPL instances. LIT in RPL cases causes to elevation and modulation of anti-inflammatory and pro-inflammatory cytokines. Our data showed that lymphocyte therapy can be proposed as an effective therapeutic agent in RPL patients with immunological background by a modulating inflammatory condition.

SARS-CoV2 infection induce miR-155 expression and skewed Th17/Treg balance by changing SOCS1 level: A clinical study.

BACKGROUND: One of the regulators in severe acute respiratory syndrome coronavirus2 (SARS-CoV2) infection is miRNAs. In COVID-19 patients, immunological responses to SARS-CoV2 infection may be impacted by miR-155, a miRNA associated to inflammation. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) of 50 confirmed COVID-19 patients /Healthy Controls (HCs) was isolated by Ficoll. The frequency of T helper 17 and regulatory T cells was analyzed by flowcytometry. The RNA was extracted from each sample and after synthesis of c-DNA, the relative expression of miR-155, suppressor of cytokine signaling (SOCS-1), Signal transducer and activator of transcription 3(STAT3), and Fork Head Box Protein 3 (FoxP3) was evaluated by real-time PCR. The protein level of STAT3, FoxP3 and RORγT in the isolated PBMCs measured by western blotting. The serum level of IL-10, TGF-ß, IL-17 and IL21 was assessed by ELISA method. RESULTS: The population of Th17 cells showed a significant rise, whereas Treg cells reduced in COVID-19 cases. The master transcription factor of Treg (FoxP3) and Th17 (RORγT) relative expression showed the same pattern as flowcytometry. STAT3 level of expression at RNA and protein level increased in COVID-19 cases. FOXP3 and SOCS-1 proteins were down-regulated. The relative expression of miR-155, up-regulated in PBMC of COVID-19 patients and revealed a negative correlation with SOCS-1. The serum cytokine profile showed a reduction in TGF-ß, on the other hand an increase was seen in IL-17, IL-21 and IL-10 in COVID-19 cases toward control group. CONCLUSION: Based on the studies conducted in this field, it can be suggested that Th17/Treg in covid-19 patients can be affected by miR-155 and it can be considered a valuable diagnostic and prognostic factor in this disease.

Comparative evaluation of autologous platelet-rich plasma and platelet lysate in patients with knee osteoarthritis.

Autologous platelet-rich plasma (PRP) and platelet lysate (PL) are nowadays promising candidates in the treatment of articular cartilage lesions. We aimed to compare PRP and PL injection effectiveness in patients with knee osteoarthritis (KOA). A total of fifty women with KOA were included in the study. Patients were treated with intra-articular injections of PRP and PL. Clinical outcomes were evaluated using the comparison of VAS, WOMAC, and ROM scores. The concentration levels of growth factors and cytokines were measured by ELISA. All patients showed significant improvements in pain and function following treatment of KOA with PL and PRP compared to baseline. Moreover, PL's concentration of growth factors was significantly higher than PRP. A significant increase was also observed in all of the aforementioned mediators in both PRP and PL products compared to control. These results can introduce PL as a promising and alternative option for KOA therapy in the future.

Application of mesenchymal stem cells (MSCs) in neurodegenerative disorders: History, findings, and prospective challenges.

Over the past few decades, the application of mesenchymal stem cells has captured the attention of researchers and practitioners worldwide. These cells can be obtained from practically every tissue in the body and are used to treat a broad variety of conditions, most notably neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Studies are still being conducted, and the results of these studies have led to the identification of several different molecular pathways involved in the neuroglial speciation process. These molecular systems are closely regulated and interconnected due to the coordinated efforts of many components that make up the machinery responsible for cell signaling. Within the scope of this study, we compared and contrasted the numerous mesenchymal cell sources and their cellular features. These many sources of mesenchymal cells included adipocyte cells, fetal umbilical cord tissue, and bone marrow. In addition, we investigated whether these cells can potentially treat and modify neurodegenerative illnesses.

The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer.

The mTOR complex 1 (mTORC1) coordinates several important environmental and intracellular cues to control a variety of biological processes, such as cell growth, survival, autophagy, and metabolism, in response to energy levels, growth signals, and nutrients. The endoplasmic reticulum (ER) is a crucial intracellular organelle that is essential for numerous cellular functions, including the synthesis, folding, and modification of newly synthesized proteins, stress responsiveness, and maintainence of cellular homeostasis. mTOR-mediated upregulation of protein synthesis induces the accumulation of misfolded or unfolded proteins in the ER lumen, which induces ER stress, leading to activation of the unfolded protein response (UPR) pathway. Reciprocally, ER stress regulates the PI3K/AKT/mTOR signaling pathway. Therefore, under pathologic conditions, the cross-talk between the mTOR and UPR signaling pathways during cellular stress can critically affect cancer cell fate and may be involved in the pathogenesis and therapeutic outcome of cancer. Here, we discuss accumulating evidence showing the mechanism of action, interconnections, and molecular links between mTOR signaling and ER stress in tumorigenesis and highlights potential therapeutic implications for numerous cancers.

Evaluation of the immune checkpoint factors in idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN), a single-organ autoimmune disease, is recognized by autoantibodies to podocyte proteins and identified as the most frequent cause of nephrotic syndrome in adults. T cells are important contributors in autoimmunity since they promote B-cell development, antibody production, direct inflammation, and organ tissue cytotoxicity. This study investigated the inhibitory immune checkpoint (ICP) receptors expressed on T lymphocytes and other immune cells. Thus, PBMCs from IMN patients were obtained before treatment, and the levels of ICPs such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin-3 (TIM-3) were examined at both gene and protein expression using real time PCR and Western blot tests respectively. The results illustrated that gene expression levels of ICPs reduced significantly in comparison to the control which were verified by related fold changes of protein expression sequentially. Our study revealed that CTLA-4, PD-1, TIM-3, and LAG-3 expression is impaired in IMN patients before treatment which could be a potential target for therapy.

Evaluation of T helper17 as skeletal homeostasis factor in peripheral blood mononuclear cells and T helper cells of end-stage renal disease cases with impaired parathyroid hormone.

BACKGROUND: Chronic renal failure is mainly connected with high and low parathyroid hormone (PTH) levels and immunological impairments. The present study aimed to evaluate T helper 17 (Th17) cells as a crucial modulator of the immune system and skeletal homeostasis in hemodialysis patients with impaired intact PTH (iPTH). METHODS: In this research, blood samples were taken from ESRD patients with high (> 300 pg/mL), normal (150-300 pg/mL), and low (< 150 pg/mL) serum intact parathyroid hormone (iPTH( levels (n = 30 in each group). The frequency of Th17 (CD4+ IL17+) cells was evaluated by flow cytometry in each group. The expression levels of Th17 cell-related master transcription factors, cytokines in peripheral blood mononuclear cells (PBMC), and Th cells, and the level of the mentioned cytokines were determined in the supernatant of PBMCs. RESULTS: The number of Th17 cells remarkably increased in subjects with high iPTH against low and normal iPTH. Also, RORÉ£t and STAT3 levels were significantly higher in high iPTH ESRD patients than in other groups in the expression of mRNA and protein levels. These findings are confirmed by evaluating the IL-17 and IL-23 in the supernatant of cultured PBMCs and isolated Th cells. CONCLUSION: Our findings indicated that increased serum PTH levels in hemodialysis cases may be involved in increasing the differentiation of CD4 + cells to Th17 cells in PBMC.

Potent SARS-CoV2-specific T-cell response in asymptomatic hemodialysis patients with hidden COVID-19 infection history.

BACKGROUND: COVID-19-related immune responses in patients with end-stage renal disease (ESRD) are characterized in detail by the humoral response, but their cellular immunity has not been clarified. Here, we evaluated virus-specific T cells in parallel with serology-related tests. METHODS: In this study, 104 ESRD patients at the hemodialysis ward of Imam Reza hospital at Tabriz (Iran) were enrolled. After blood sampling, SARS-CoV2-specific humoral and cellular immune responses were evaluated by SARS-CoV2-specific IgM/IgG ELISA and peptide/MHCI-Tetramers flow cytometry, respectively. RESULTS: Our results showed that 14 (13.5%) and 45 (43.3%) patients had specific SARS-CoV2 IgM and IgG in their sera, respectively. Immunophenotyping for SARS-CoV2-specific CD8+ T lymphocytes revealed that 68 (65.4%) patients had these types of cells. Among SARS-CoV2-specific CD8+ T lymphocytes positive subjects, 13 and 43 individuals had positive results for specific SARS-CoV2 IgM and IgG existence, respectively. Also, there was a relationship between specific SARS-CoV2 IgM (p = 0.031) and IgG (p < 0.0001) existence and having SARS-CoV2-specific TCD8+ lymphocytes in the studied population. CONCLUSION: Despite not having clinical symptoms, a high rate of SARS-CoV2-specific T-cell response in asymptomatic ESRD patients may reveal a high burden of asymptomatic COVID-19 infection in these patients.

Sirolimus- and cyclosporine-loaded nanostructured lipid carriers: Development, characterization, and in vitro evaluation in T-cell profiles of patients with a history of recurrent pregnancy loss.

Purpose: The authors developed nanostructured lipid carriers (NLCs) loaded with sirolimus (SRL) and cyclosporine (CsA) to improve their therapeutic efficacy in recurrent pregnancy loss (RPL) patients. Methods: Mono-delivery and co-delivery of SRL and CsA by NLCs (S-NLCs, C-NLCs, and S-C-NLCs) were developed. The MTT assay was used to study the optimum dose of formulations. PCR, Western blotting, and ELISA were also conducted. Results: Well-designed nanodrugs with a suitable size, zeta potential, desirable encapsulation efficiency drug loading, and cellular uptake confirmed optimum formulations. Based on cell viability, the amounts of SRL and CsA could be reduced greatly due to the co-delivery by NLCs. Following S-NLCs and C-NLCs interventions in T cells of patients with RPL and immune abnormality, a significant difference was observed in transcription factors and cytokine levels of Th1, Th17, and Tregs compared with healthy samples. Thus, a higher level of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17, and IL-21) and their regulators (T-bet and RORγt), as well as a lower level of an anti-inflammatory cytokine (IL-10) and its regulatory (Foxp3), were observed. However, no significant difference was found following the S-C-NLCs intervention. Conclusions: S-C-NLCs effectively balance the immune responses in peripheral T cells in RPL patients to induce maternal immune tolerance.

The immunomodulatory effect of intradermal allogeneic PBMC therapy in patients with recurrent spontaneous abortion.

BACKGROUND: There has been limited study on the impact of PBMC therapy in RSA patients with immunological disorders such as Th17 and Treg cell dysregulation, as well as their associated factors. This study aimed to assess the efficacy of PBMC therapy in modulating immune cell frequency, cytokine production, transcription factors, and miRNAs implicated in the regulation of their function, as well as their potential superiority to routine treatments. METHODS: Fifty RSA women who had received PBMCs and 50 matched-paired control RSA women who had received the routine treatments were recruited and followed for three months. The frequencies of Th17, Treg, NK, and B cells were assessed using flow cytometry. Thereafter, the gene expression level of the transcription factors and related miRNAs of Treg cell and Th17 cell was quantified using RT-PCR. Then ELISA was employed to assess the cytokine production of Th17 and Treg cells. Finally, the live birth rate and miscarriage rate were evaluated as clinical outcomes in this study. RESULTS: Flow cytometry analysis revealed that PBMC therapy significantly reduces the frequencies of Th17 and NK cells while enhancing the frequency of Treg cells. RT-PCR analysis confirmed that PBMC therapy significantly downregulates RORγt and upregulates FoxP3. Likewise, RT-PCR analysis showed that PBMC therapy reduces the expression of miR-25, miR-155, and miR-326 while increasing the expression of miR-10a. ELISA results demonstrated that PBMC therapy considerably decreases the concentration of inflammatory cytokines IL-1ß, IL-17, and TNF-α and enhances the concentration of anti-inflammatory cytokines IL-10 and TGF-ß. Following PBMC therapy live birth rate raised while miscarriage rate reduced. CONCLUSION: Our findings suggested that, in contrast to routine treatments, PBMC therapy can significantly modulate the maternal immune system by enhancing the Treg/Th17 paradigm and regulating the expression of Treg and Th17 cell-associated cytokines, transcription factors, and miRNAs. This treatment also can increase the live birth rate in RSA patients.

The evaluation of CD39, CD73, and HIF-1 α expression besides their related miRNAs in PBMCs of women with recurrent pregnancy loss.

The molecular mechanisms involved in the pathogenesis of recurrent pregnancy loss (RPL) are not completely recognized. The present study aimed to assess the molecules associated with ATP catabolism and hypoxia besides their related miRNAs in patients with RPL. The frequency of Th17 and Treg cells in PBMCs of RPL women and healthy pregnant women were evaluated with Flow cytometry. The expression levels of CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-1α), miR-18a, miR-30a, and miR-206 in PBMCs of two groups were measured with real-time PCR and western blotting. Then, serum levels of IGF-1, TGF-ß, and HIF-1α were measured by ELISA. Our results indicated a higher (p = 0.0002) and lower (p < 0.0001) frequency of Th17 and Treg lymphocytes in RPL women, respectively. The expression level of CD39 decreased in PBMCs of RPL women whereas the level of CD73 and HIF-α increased (p = 0.0010, 0.0023, 0.0006 respectively). The results of CD39 and CD37 were also confirmed by protein analysis (p = 0.0047, 0.0364 respectively). Almost, the same results for CD39 and CD73 expression at mRNA and protein levels were observed in isolated Treg cells. Moreover, we found the higher expression of miR-206 and miRNA-30a (p = 0.0038, 0.0123), but the lower expression of miRNA-18a (p = 0.0101) in RPL. The concentration level of IGF-1, and TGF-ß reduced (p = 0.0017, 0.0065 respectively) while the level of HIF-α elevated (p = 0.0235) in serum samples of RPL. In conclusion, we observed the dysregulation of molecules that are involved in ATP catabolism and hypoxia, including CD39, CD73, and HIF-1a which is related to miR-18a, miR-30a, and miR-206 change in RPL women. It may be potentially used for RPL prognosis by more comprehensive future studies.

Randomized double-blinded controlled trial on the effect of synbiotic supplementation on IL-17/IL-23 pathway and disease activity in patients with axial spondyloarthritis.

BACKGROUND: Interleukin 17 (IL17)-expressing CD4+ T cells and IL-17/IL-23 pathway play a key role in the pathogenesis of axial spondyloarthritis (axSpA). Synbiotics have been suggested due to their immunomodulatory effects in the treatment of autoimmune diseases. This randomized double-blind, placebo-controlled trial was designed to assess the effects of synbiotic supplement on IL-17/IL-23 pathway and disease activity in patients with axSpA. METHODS: Forty-eight axSpA patients were randomly allocated to use one synbiotic capsule or placebo daily for 12 weeks. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and ASAS-endorsed disease activity score-C-reactive protein (ASDAS-CRP). The secondary outcome was proportion of IL17-expressing CD4+ T cells, IL-17 and IL-23 gene expression, and supernatant levels of IL-17 and IL-23, which were measured at the baseline and end of the trial. RESULTS: A total of 48 patients were randomized into the synbiotic and placebo groups. Thirty-eight patients completed the study. Synbiotic supplementation significantly reduced the proportion of IL17-expressing CD4+ T cells (4.88 ± 2.47 vs. 2.16 ± 1.25), gene expression of IL-17 (1.03 ± 0.24 vs. 0.65 ± 0.26) and IL-23 (1.01 ± 0.13 vs. 0.68 ± 0.24) and serum IL-17 (38.22 ± 14.40 vs. 24.38 ± 11.68) and IL-23 (51.77 ± 17.40 vs. 32.16 ± 12.46) compared with baseline. Significant differences between groups were noticed only in the proportion of IL17-expressing CD4+ T cells, and IL-17 and IL-23 gene expression. Synbiotic supplementation did not significantly alter BASDAI and ASDAS-CRP compared with baseline and placebo group at the end of trial. CONCLUSION: Present study indicated beneficial effect of synbiotic supplement on IL-17/IL-23 pathway without improving disease activity in axSpApatients.HighlightsSynbiotic supplementation reduced IL17-expressing CD4+ T cells proportion in axSpA.Synbiotic supplementation decreased IL-17 and IL-23 gene expression in axSpA.Synbiotic supplementation did not change disease activity score in axSpA.

Preeclampsia-Derived Exosomes Imbalance the Activity of Th17 and Treg in PBMCs from Healthy Pregnant Women.

The disturbance of maternofetal immune tolerance is identified as one of the important issues in the pathology of preeclampsia (PE). PE exosomes are believed to possess significant roles in immune abnormalities. In this study, to assess the possible effects of PE exosomes in the pathophysiology of preeclampsia patients, exosomes were isolated from the serum of PE patients and incubated with peripheral blood mononuclear cells (PBMCs) of healthy pregnant women. Also, exosomes from healthy pregnant women were utilized as the control. Th17/Treg ratio in PE and healthy pregnant women and the effects of PE exosomes on expression level of Th17 and Treg transcription factors, as well as their related cytokines in PBMCs of healthy pregnant women, were evaluated. A significant decrease in Treg cell number and increase in Th17 cells and Th17/Treg ratio were observed in PE patients. Following PE-exosome intervention, a significant increase in mRNA expression level of RORγt, IL-17, IL-23, IL-1ß, and IL-6, and significant decrease in IL-10 and TGFß were evident. On the other hand, no significant difference in FoxP3 level was detected. Additionally, increased IL-6, IL-17, IL-23, and IL-1ß levels and decreased IL-10 level in the supernatant of cultured PBMCs from healthy pregnant women following PE-exosome intervention were exhibited. However, TGF-ß level did not change significantly. Based on our findings, PE exosomes are able to alter the activity of Th17 and Treg cells as well as their related gene expression and cytokine profiles. These findings support the probable role of PE exosomes in PE pathogenesis.

Role of miRNAs interference on ovarian functions and premature ovarian failure.

Premature ovarian failure is a to some extent unknown and intricate problem with diverse causes and clinical manifestations. The lack of ovarian sex hormones presumably is effective in the occurrence of ovarian failure. Our progress in this field has been very little despite undertaken scientific research endeavors; scholars still are trying to understand the explanation of this dilemmatic medical condition. In contrast, the practice of clinical medicine has made meaningful strides in providing assurance to the women with premature ovarian insufficiency that their quality of life as well as long-term health can be optimized through timely intervention. Very recently Scientists have investigated the regulating effects of small RNA molecules on steroidogenesis apoptosis, ovulation, gonadal, and corpus luteum development of ovaries. In this literature review, we tried to talk over the mechanisms of miRNAs in regulating gene expression after transcription in the ovary. Video abstract.